Updates to vaccine recommendations focus of ACIP's June meeting

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July 06, 2015

Summary of discussions from June 24–25 meeting

CDC’s Advisory Committee on Immunization Practice (ACIP) met in Atlanta on June 24–25 to discuss vaccine recommendations. Complete minutes of the meeting will be published on the CDC National Immunization Program website at: www.cdc.gov/vaccines/acip/index.html. Following is a summary of the committee's discussions.

Meningococcal vaccines

Two meningococcal B vaccines have been approved by the FDA for use in the United States, Trumenba (Pfizer) and Bexsero (Novartis), with both being approved for persons aged 10–25 years. The ACIP working group has reviewed data on these vaccines and has applied the GRADE analysis.

The ACIP previously recommended use in high-risk patients (i.e., compliment deficiencies, persons presently taking eculizumab [Soliris—Alexion], persons that are asplenic, microbiologists, and those exposed during outbreaks of disease), and now is considering use in other groups. Issues in making a recommendation include incomplete data on effectiveness, strain coverage, duration of protection, carriage, and herd immunity. Also, at this time, the burden of disease is low.

A GRADE (Grading of Recommendations Assessment, Development, & Evaluation) analysis was applied. The lack of data has made this process very difficult. The two available vaccines have completely different antigens, which require different methods to access breadth of coverage of the different strains of meningitis B, so each vaccine had to be considered individually. Also, since the incidence of disease is low, immunogenicity studies were used to estimate efficacy. MenB-4C (Bexsero) demonstrated short-term immunogenicity (persistence 11–23 mo) with an efficacy range of 63%–94%. It has not been studied for use with other vaccines. The MenB-FHbp (Trumenba) has demonstrated short-term immunity (up to 48 mo) with an efficacy of approximately 81%–84%, and had been studied for concomitant use with other adolescent vaccines. Again, all the evidence is not optimal for a good evaluation.

Considerations for use in adolescents were discussed. Incidence of disease is low with estimates of 55–65 cases annually in persons aged 11 to 24 years with 5–10 deaths. Over the last 2 years, there have been several university outbreaks with approximately 34 cases and 4 deaths due to meningococcal B. This shows that the incidence in college and noncollege students is similar. Studies were conducted during the Princeton outbreak mass vaccination campaign with Bexsero. The workgroup concluded the immunogenicity waned within 6 months after dose three, but appeared to stabilize for 6–48 months. The adverse effect complaints were common, but the reactions were self-limited. Cost-effectiveness analysis showed the number needed to treat (NNT) to prevent one case ranged from approximately 100,000 to 400,000. The cost per quality-adjusted life–year (QALY) was estimated to be $3.7 million to $9.4 million, which is much higher than any other recommended vaccine. The workgroup gave the GRADE analysis a category B recommendation (permissive, not routine).

Again, this is based upon limited data, the proportions of serogroup B cases that could be prevented is unknown, limited effectiveness data are available, the impact of coverage is unknown, and therefore, the impact of vaccination is unknown. The workgroup concluded that meningococcal disease is rare, however life-threatening. While key data are lacking, there is a high desire by the population for access to these vaccines.

The policy statement that was approved reads:

A serogroup B meningococcal (MenB) vaccine series may be administered to adolescents and young adults 16 through 23 years of age to provide short-term protection against most strains of serogroup B meningococcal disease. The preferred age for MenB vaccination is 16 through 18 years of age (Category B).

Influenza update

The effectiveness of influenza vaccines is monitored by five sites around the country and is called the U.S. Flu VE Network. Influenza A(H3N2) predominantly circulated this last year. Most of these viruses (80%) were antigenically drifted from the vaccine component. Eighty-three percent (83%) of the positive samples were influenza A(H3N2) and 17% were influenza B viruses. The overall adjusted vaccine effectiveness was 23%, with 13% against A(H3N2), 55% against B-Yamaga strains, and 63% against B-Victoria strains. The A(H1N1) did not circulate to any extent this year. Again, the A(H3N2) virus that primarily circulated had drifted this year, and the low effectiveness of vaccine was expected.

A quadrivalent, intradermal influenza vaccine by Sanofi-Pasteur recently was approved by FDA.

Trials demonstrated that the safety and efficacy was similar to the trivalent intradermal influenza vaccine. This will replace the trivalent vaccine, and is expected to be available in the fall of 2015.

The ACIP has had no preferential recommendations for high-dose (HD) versus standard-dose (SD) influenza vaccine since it was approved in 2009. One study has been published that shows a 24.2% relative efficacy of HD over SD. A GRADE analysis had been applied to see if the benefits and harms favor HD over SD. It will be presented when it is completed. The ACIP removed the preferential recommendation for live attenuated influenza vaccine (LIAV) for children at the February 2015 meeting.

The composition for the 2015–16 vaccine has been approved by the FDA Vaccine and Related Biologic Products Advisory Committee (VRBPAC). The A(H3N2) and B-Yamagata Strain has been changed. New license has been approved for Fluzone Quadrivalent Intradermal IIV, an expanded age (18 y and older) for Flublok (Protein Sciences), and approval of Afluria (bioCSL) for injection by jet injector (Stratus by Pharmajet). The algorithm for vaccination of children up to age 8 years was presented for vote. If they had two or more doses of any vaccine in any previous season, then they only need one dose this year. If not, or they do not know, then two doses should be given. These two doses do not need to have been received during the same season.

Influenza A (H5N1) vaccine

Influenza H5N1 continues to circulate with a large upsurge in human cases in Egypt, along with a significant effect on poultry. These increases in human cases are caused by an increase in persons exposed to infected poultry, not person-to-person spread. There are reports of H5-infected birds in Canada and the United States; H5N1, H5N8, and H5N2 are highly pathogenic in chickens. A new H5N1 vaccine, Q-Pan (GlaxoSmithKline), provides protection against most of the human viruses based upon immunological assays, but does not appear to be cross reactive against the H5N2 and H5N8 poultry viruses. The Q-Pan vaccine should be available in 2017.

Pneumococcal vaccines

There have been multiple recent recommendations for the use of pneumococcal polysaccharide vaccine (PPSV23) and pneumococcal conjugate vaccine (PCV13). These recommendations have included complicated interval recommendations. The ACIP pneumococcal working group has been reviewing data to see if intervals could be simplified and harmonized among the different age and risk groups.

It is recommended that PCV13 be administered before PPSV23. The current interval for ages 2–64 years is ≥ 8 weeks. The interval for those older than 65 years is 6–12 months; however,, there are no data for shortening the interval, and CMS only pays for the second vaccine if 1 year has passed. Most trials were not designed to discover the optimal interval; however, there appears to be no immunological differences between the longer and shorter intervals, and adverse effects were increased with shorter intervals. Data among all ages demonstrated no blunting of effect if vaccines are separated by 1 year. Given the lack of direct comparison studies, programmatic issues become important in the decision to make a change. The ACIP voted to not make changes to the pediatric schedule and make the adult change from 6–12 months to 1 year as seen in the following table (in bold):

Adults > 65 years of age with no previous pneumococcal vaccine (PCV13 or PPSV23):

A dose of PPSV23 should be given at least 1 year following a dose of PCV13. The two vaccines should not be coadministered. If a dose of PCV23 is given earlier than the regular interval, the dose need not be repeated.

It should be noted that PCV13 is not indicated for adults with medical conditions that are not listed in the above table. Persons in this group (e.g., patients with pulmonary disease, cardiovascular disease, diabetes, and other select conditions and risks) are recommended to receive PPSV23 only.

Combination vaccines

Quadracel DTaP-IPV vaccine (Sanofi Pasteur) has been approved by the FDA for use in children aged 4–6 years. It is indicated for the fifth dose in the DTaP series and the fourth or fifth dose in the IPV series.

A new hexavalent pediatric vaccine DTaP-IPV-Hib-HepB (Merck and Sanofi Pasteur) is under review by FDA and is expected to be approved later this year and brought to ACIP at its October meeting.

Human papilloma vaccine (HPV)

In February, ACIP recommended the use of HPV9 as one of the available HPV vaccines for use in males and females. Even though HPV9 is only FDA approved for boys aged 9–15 years, ACIP still recommends it be administered up to age 21 years (26 y for HIV-infected males and men who have sex with men [MSM]). This recommendation did not include the use of HPV9 in individuals that have completed the series with one of the other available vaccines. Merck expects HPV4 to be on the market until mid-2016. Cost analysis demonstrated HPV9 was cost saving when it is given instead of HPV4; however, the addition of HPV9 to those who already had received HPV4 was much higher ($117,400–$156,000 per QALY) and not thought to be cost effective.

Given the cost of the additional vaccination and the low coverage of the routine recommended series, ACIP felt more effort should be put toward raising the HPV9 rates in those who have not completed the series instead of giving additional doses. New guidance was developed for those who start the series with the HPV2 or HPV4. HPV9 can be used to complete the series, but ACIP has no recommendation for additional doses of HPV9 for those who have completed the series.

Pertussis vaccine

FDA and ACIP currently recommend a single dose of tetanus–diphtheria–pertussis (Tdap) vaccine for use in most adults. One exception is an off-label recommendation is for vaccination of pregnant women with every pregnancy. It has been suggested that revaccination with Tdap of close contacts to newborns should be considered. With increasing pertussis rates in the United States, differing strategies do not appear to be effective. Recent evidence shows that siblings are the primary source of exposure of infants, even though they are vaccinated in most cases. Rates of vaccination of pregnant women are low, ranging from 13%–23%. However, vaccine effectiveness is high with maternal vaccination. It was felt that increasing efforts to get pregnant women vaccinated would be more effective than vaccinating close contacts. Adult vaccination rates are also very low, and efforts could be increased for routine adult vaccinations.

There are multiple possible reasons for the increase in pertussis rates. These include possible surveillance bias, waning immunity to vaccination, and genetic changes in Bordetella pertussis. One such genetic change is the appearance of a pertactin-deficient pertussis bacterial, a component of the vaccine. Vermont has a very high pertussis attack rate, and has found that 95% of its cultures showed pertactin-deficient pertussis. A study of cases who have competed their DTaP series resulted in a vaccine effectiveness (VE) of 84% overall, with a decreasing VE over time. A similar Tdap study showed a VE of 70%, again decreasing over time. When stratified by pertactin strains, VE was 51%; however, the confidence intervals overlapped, suggesting that pertactin deficiency may not affect vaccine effectiveness statistically.

Herpes zoster vaccine

The annual rate of herpes zoster (HZ) in the United States is approximately 4 per 1,000 population per year (1 million people per year). The age-adjusted rates appear to be increasing. The herpes zoster vaccine was licensed in 2006, with a sluggish uptake for multiple reasons.

An investigational inactive herpes zoster vaccine from GlaxoSmithKline is now under review by FDA. The efficacy and safety studies were reviewed. The original study was published in the New England Journal of Medicine on May 28, 2015. The vaccine showed an efficacy of 97.2% for the prevention of HZ in adults older than 50 years, and did not vary based upon age. The efficacy did not wane over the 3.2 years of follow-up. With local adverse events common within 7 days of vaccination, most were mild to moderate and of short duration. More studies are expected.

Smallpox vaccine

The smallpox working group has been evaluating the 2001 recommendations for the use of smallpox vaccine. Currently, it is recommended for use in laboratory workers with potential exposure risk. In 2007, DryVax, the only available vaccine at the time, was replaced with ACAM200 (Sanofi Pasteur) as the only available vaccine approved in the United States since that time. The working group has been discussing recommendations for nonemergent use of ACAM2000.

Smallpox (Variola) is one of four species of the family Poxviridae. The other pox viruses known to infect humans is Vaccinia (Vaccine Strain), Monkeypox, and Cowpox. Various vaccines have been used in the past with varying degrees of attenuation and safety profiles. There was a high incidence of serious adverse events with vaccination with Dryvax, but fewer adverse events with revaccination. The incidence of adverse events has decreased with recent use due to better screening. ACAM2000 was derived from a clonal isolate of Dryvax, and is administered with a bifurcated needle.

A GRADE analysis has been developed for the use of ACAM2000 smallpox vaccine for use routinely in persons at risk for occupational exposure. A review of available studies showed no reports of serious adverse events (i.e., death, eczema vaccinatum, progressive vaccinia or postvaccinial encephalitis) except for myocarditis/pericarditis, which was similar to Dryvax; however, the clinical trials were not powered to detect clinical significance. There have been 26 reported exposure incidents, resulting in 14 infections (54%). The working group recommended extending the current ACIP recommendations to include ACAM2000 vaccine for laboratory workers and health care workers at risk for exposure to these viruses. Persons who administer smallpox vaccine can be offered vaccination. A concern was expressed that today’s persons receiving vaccines are receiving the vaccine for the first time, which carries more risk, unlike in 1980, when most were revaccinated and had received smallpox vaccine when they were younger. Changes to the recommendations were approved by the committee.

General recommendations

The ACIP General Recommendations working group has presented most of the revised sections over the last few years. The second half of the document was presented to ACIP for approval. These sections include Altered Immunocompetence, Special Situations, Vaccination Records, Vaccination Programs, and Vaccine Information Sources.

ACIP revised some guidelines in the section on Altered Immunocompetence based upon the IDSA Clinical Practice Guidelines published in 2013. New conditions, medications, and combination therapies were added to this section, as well as guidelines of when to withhold select vaccines, including both live and inactivated vaccines. As mentioned in previous meeting reports, both “high-level immunosuppression” and “low-level immunosuppression” categories were added. Also, a section was added to use Altered Immunocompetence as an indication to administer a vaccine outside of normal schedules.

The Special Situations section had some new revisions, since previously discussed, to add the Tdap in pregnancy recommendations. More information was added to the Vaccine Programs section about Immunization Information Systems (IIS) and the new National Vaccine Adult Standards.

The ACIP voted to approve the document in its entirety.

The next meeting of ACIP is scheduled for October 21–22, 2015.

Stephan L. Foster, PharmD, FAPhA, FNAP, Professor, University of Tennessee College of Pharmacy, Memphis; APhA Liaison Representative, ACIP; and CAPT (Ret), U.S. Public Health Service